New 16-substituted-19-norpregna-1, 3, 5(10), 6, 8-pentaen-20-ones



United States Patent This invention relates to new aromatic steriods.More particularly, it relates to novel steroids of the pregnane serieshaving aromatic rings A and B and methods of preparing the same.

The novel steroids of the present invention may be illustrated by thefollowing formula;

wherein R is selected from the group consisting of hydrogen and loweralkanoyl; R is selected from the group consisting of hydrogen,fluoromethyl, difluoromethyl and trifluoromethyl; R is selected from thegroup consisting of hydroxyl and lower alkanoyloxy; R is hydroxyl, and

R R taken together represent lower alkylidenedioxy and R is selectedfrom the group consisting of halogen,

hydroxyl, lower alkanoyloxy, and lower alkylsulfonyloxy.

The novel steroids of the present invention are substantially insolublein Water and somewhat soluble in the usual organic solvents.

The starting materials in preparing the present compounds may beillustrated by the formula;

wherein R R and R are as defined above and R is hydrogen,(a)-fluoromethyl, (a)-difiuoromethyl, and (u)-trifluoromethyl.

The specific intermediates found useful in the process of this inventioninclude:

16u,21-diacetoxy-9a,1lB-dichloro-l7a-hydroxypregna-1,4-

diene-3,20-dione;

21-acetoxy-9 a, 11,8-dichloro-l6a,l7u-isopropylidenedioxypregna-1,4-diene-3 ,20-di0ne;

904,1lfl-dichloro-21-hydroxy-16a,l7a-isopropylidenedioxy' pregna-l,4-diene-3,20-dione;

2l-acetoxy-9a11,Q-dichloro-6a-fluoromethyl-16:1,17aisopropylidenedioxy-pregna-1,4-diene-3,20-dione;

See

21-acetoxy-9ix, l 1[3-dichloro-6ix-difluoromethyl-16a,17a-

isopropylidenedioxypregna-1,4-diene-3,20-dione;

2l-acetoxy-l 6a,17oc-piOPYlld61'l6dlOXY-9a,1lp-dichloropregna-1,4-diene-3,20-dione;

21-methanesulfonyloxy-9a,11,8-dicl1lorol6u,l7a-isopropylidenedioxypregna-1,4-diene-3,20-dione;

and the like.

The process of the present invention is carried out by contacting thestarting material with a weak base. The weak base may be for exampledimethyltormamide, pyridine, collidine, lutidine and the like. Thetemperature of the reaction may vary from about 15 C. to about 160 C.The time for completing the reaction will depend on the temperature usedand may vary from about one-half hour to about 72 hours. Aftercompletion of the reaction, the desired steroids may be recovered bymethods well known in the steroid art.

The compounds of the present invention are active in reducingcholesterol and therefore have utility as hypocholesteremic agents. Thecompounds also have no appreciable activity as estrogens. This lack ofestrogenic activity makes them useful as hypocholesteremic agentswithout the undesirable estrogenic feminizing side-effects.

The following examples illustrate in detail the preparation ofrepresentative steroids of the present invention.

EXAMPLE 1 Preparation 0] 911,1 1 [3-dichl0r0-1 6a,]7a-isopr0pylidenedzoxy-Zl -met/zanesulfonyloxypregiza-l,4-diene3,20-dione A solution of904,1l,8-dich1oro-2l-hydroxy-16u,17aisopropylidenedioxypregna-1,4-diene-3,20-dione(0.72 g.) (Steroids, l, 331 (1963)] in cold pyridine (7 ml.) is treatedwith methanesulfonyl chloride (0.15 ml.) and allowed to stand at 5 C.for 16.5 hours. The reaction mixture is then poured into ice water andthe resultant precipitate (0.75 g., melting point 212-214 C., dec.) isfiltered and washed well with Water. Crystallization from acetone-hexanegives the product of the example (0.65 g., melting point 223.5 226 C.,dec.). A portion of the latter is crystallized three more times from thesame solvents to give melting point 232-234 C., dec.

EXAMPLE 2 Preparation of 21 -chloro-3-hydroxy-J6a,1 7a-is0propylidene-aioxy-19-n0rpregna-1 ,3,5 (1 0) ,6,8-pentaen-20-one A solution of9a,llli-dichloro-lot,17a-isopropylidenedioxy-2l-n1ethanesulfonyloxypregna=1,4-diene-3,20dione (0.50 g.) and lithium chloride (0.14 g.) in dirnethylformamide (25ml.) is heated under reflux for 0.5 hour. The yellow solution isconcentrated under reduced pressure to near dryness, water is added andthe product is filtered and Washed with water to give an amorphousyellow solid (0.38 g), melting point 90-l5 0 C. The product is solutalein 10% sodium hydroxide solution and exhibited an equilenin-typeabsorption in the ultraviolet. A portion (0365 g.) is dissolved inbenzene (ca. 10 ml.) and adsorbed on a synthetic magnesium silicate(14.5 g.) column. Elution with 3% acetone-petroleum ether (boiling point-70") gives the product of the example (0.264 g); A 231 m (568,900),269m (66570), 281 m (E6570), 293 m (@4800), 328 mu (63200) and 342 mi(63200). The product, obtained as a white amorphous solid, is apparentlyliable to air or light. A solution of the product (0.13 g.) in pyridine(2 ml.) and acetic anhydride (1 ml.) is allowed to stand at roomtemperature for 19 hours. The solution is poured into ice water, theprecipitate is filtered and washed with water to give (0.127 g.) ofproduct, melting point 200-203.5 C. Two crystallization fromacetone-hexane gives the analytical sample (0.109 g.) of

3-acetoxy-21-chloro-16a,17ot-isopropylidene dioxy 19-norpregna-1,3,5,(l),6,8-pentaen 20 one, meltaing point 205 -207 C.

EXAMPLE 3 Preparation of 1 60:,21 -a'iaceroxy-3,l7a-dihydr0xy-1 9-norpregna-1,3,5 (l0) ,6,8,-pentaen-20-0ne One gram of16a,21-diacet0xy-9a,llfi-dichloro-lhhydroxypregna 1,4 diene 3,20-di0ne[Ster0ids, 1, 331 (1963)] in 50 ml. of dimethylformamide is reacted andworked up in the manner described in Example 2 above. The crude productis isolated, chromatographed, and crystallized from acetone-hexane togive 16a,21|-diacetoxy- 3,l7a-dihydroxy-19-norpregna 1,3,5 (),6,8pentaen- 20-one.

Saponification of the product of the example with potassium carbonate inmethanol followed by acidification gives3,l6u,l7a,2l-tetrahydroxy-l9-norpregna-1,3,5(10), 6,8-pentaen-20-one.

EXAMPLE 4 Preparation of 21 -acet0xy-3 -hydr0xy-l 6 ot,1 7a-isopropylidenedioxy-l9-norpregna-1,3,5, (10 ,6,8-pentaen-20-0nePreparation of 21-acet0xy-6-fluoromethyl-3-hydroxy-16a,

17a isopropylidenedi0xy-19-n0rpregna-1,3,5,(10),6,8- penlaen-ZO-oneFollowing essentially the procedure of Example 2, the steroid21-acetoxy-9a,11fi-dichloro-6a-fiuoromethyl 16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione (US. Patent 3,038898)on being heated in dimethylformamide is converted into the product ofthe example.

EXAMPLE 6 Preparation of 2] aceloxy-6-diflu0romethyl-3-hydr0xy- 16a,17otisopropylidenedioxy-l9-n0rpregna-l,3,5(10), 6,8-pentaen-20-0ne Followingessentially the procedure of Example 2, the steroid 21-acetoxy-9a, l1fl-dichloro-6 ot-difiuoromethyl- 1 6oz,l,7a-isopropylidenedioxypregna-l,4-diene-3,20-dione (US. Patent3,038,898) on being heated in dimethylformamide is converted into theproduct of the example.

4 EXAMPLE 7 Preparation of 21-acetoxy-6-triflu0r0methy-l-3-hydroxy- 16a,] 7 0c isopropylidenedi0xy-19norpregna-1,3,5(10), 6,8-pentaen-20-0neFollowing essentially the procedure of Example 2, the steroid 2l-acetoxy:,11/3 dichloro-6a-triflu0romethyl-16a,l7a-isopropylidenedioxypregna-l,4-diene-3,20 dione (US. Patent3,038,898) on being heated in dimethylformamide is converted into theproduct of the example.

We claim:

1. A steroid of the formula:

wherein R is selected from the group consisting of hydrogen and loweralkanoyl; R is selected from the group consisting of hydrogen,fiuoromethyl, difluoromethyl and trifiuoromethyl; R is selected from thegroup consisting of hydroxyl and lower alkanoyloxy; R is hydroxyl and RR taken together represent lower alkylidenedioxy and R is selected fromthe group consisting of halogen, hydroxyl, lower alkanoyloxy and loweralkylsulfonyloxy.

2. The compound, 3,16a,17a,21-tetrahydroxy-19-norpregna-1,3,5 l0),6,8-pentaen-20-one.

3. The compound 1611,21-diacetoxy-3,17a-dihydr0xy- 19-norpregna-1,3,510) ,6,8-pentaen-20-one.

4. The compound 21-acetoxy-3-hydroxy-l6a.,l7a-isopropylidenedioxy 19norpregna 1,3,5 (10),6,8-pentaen- 20-one.

5'. The compound3,21-dihydroxy-16a,17a-isopropylidenedioxy-19-norpregna-1,3,5lO),6,8-pentaen-20-one.

6. The compound 21-chloro-3-hydroxy 16a,l7a isopropylidenedioxy 19norpregna 1,3,5 (10),6,8 pentaen-20-one.

7. The compound 21 acetoxy 6 fiuoromethyl-Ei-hydroxy 16a,17 xisopropylidenedioxy l9 norpregna- 1,3,5 10) ,6,8-pentaen-20-one.

8. The compound 2l-acetoxy-6-difiuoromethyl 3 hydroxy 16a,17otisopropylidencdioxy l9 norpregna- 1,3,5(10),6,8-pentaen-20-one.

9. The compound 2l-acetoxy-6-trifluoromethyl-3-hydroxy l6a,l7otisopropylidenedioxy 19 norpregna- 1,3,5 10) ,6,8-pentaen-20-one.

No references cited.

LEWIS GOTTS, Primary Examiner.

1. A STEROID OF THE FORMUAL: